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Osteoarthritis (OA) is a joint disease common worldwide. Currently, no disease-modifying osteoarthritis drugs (DMOADs) have successfully passed clinical trials, often due to a lack of cartilage penetration. Thus, targeting the extracellular matrix (ECM) is a major priority. The design of cartilage-targeting drug delivery systems (DDSs) for intra-articular administration requires consideration of the physicochemical properties of articular cartilage, such as its porosity and negative fixed charge. Various positively charged biomaterials such as polyaminoacids, proteins, polymers, and lipids can be used as DDSs to enhance cartilage penetration. Cationic nanocarriers interact electrostatically with anionic glycosaminoglycans of the ECM, ensuring passive cartilage-targeting penetration and prolonged retention. Active targeting strategies involve DDSs surface decoration using antibodies or peptides with a strong affinity for collagen II and chondrocytes in the cartilage. This review presents all the relevant bio-physicochemical properties of healthy and OA cartilages, as well as state-of-the-art intra-articular cartilage-targeted DDSs, intending to better understand the recent advances in the application of cartilage-targeting delivery systems for OA therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Mesenchymal stem cell (MSC) therapy shows promise in regenerative medicine. For osteoarthritis (OA), MSCs delivered to the joint have a temporal window in which they can secrete growth factors and extracellular matrix molecules, contributing to cartilage regeneration and cell proliferation. However, upon injection in the non-vascularized joint, MSCs lacking energy supply, starve and die too quickly to efficiently deliver enough of these factors. To feed injected MSCs, we developed a hyaluronic acid (HA) derivative, where glucose is covalently bound to hyaluronic acid. To achieve this, the glucose moiety in 4-aminophenyl-β-D-glucopyranoside was linked to the HA backbone through amidation. The hydrogel was able to deliver glucose in a controlled manner using a trigger system based on hydrolysis catalyzed by endogenous ß-glucosidase. This led to glucose release from the hyaluronic acid backbone inside the cell. Indeed, our hydrogel proved to rescue starvation and cell mortality in a glucose-free medium. Our approach of adding a nutrient to the polymer backbone in hydrogels opens new avenues to deliver stem cells in poorly vascularized, nutrient-deficient environments, such as osteoarthritic joints, and for other regenerative therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Osteoarthritis is the most common chronic joint disease and a major health care concern due to the lack of efficient treatments. This is mainly related to the local and degenerative nature of this disease. Kartogenin was recently reported as a disease-modifying osteoarthritis drug that promotes cartilage repair, but its therapeutic effect is impeded by its very low solubility. Therefore, we designed a unique nanocrystal-chitosan particle intra-articular delivery system for osteoarthritis treatment that merges the following formulation techniques: nanosize reduction of a drug by wet milling and spray drying. The intermediate formulation (kartogenin nanocrystals) increased the solubility and dissolution rates of kartogenin. The final drug delivery system consisted of an easily resuspendable and ready-to-use microsphere powder for intra-articular injection. Positively charged chitosan microspheres with a median size of approximately 10 µm acted as a mothership drug delivery system for kartogenin nanocrystals in a simulated intra-articular injection. The microspheres showed suitable stability and a controlled release profile in synovial fluid and were nontoxic in human synoviocytes. The cartilage retention skills of the microspheres were also explored ex vivo using cartilage. This drug delivery system shows promise for advancement to preclinical stages in osteoarthritis therapy and scale-up production., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Clostridioides difficile infection (CDI) is a critical nosocomial infection with more than 124,000 cases per year in Europe and a mortality rate of 15-17 %. The standard of care (SoC) is antibiotic treatment. Unfortunately, the relapse rate is high (∼35 %) and SoC is significantly less effective against recurrent infection (rCDI). Fecal microbiota transplantation (FMT) is a recommended treatment against rCDI from the second recurrence episode and has an efficacy of 90 %. The formulation of diluted donor stool deserves innovation because its actual administration routes deserve optimization (naso-duodenal/jejunal tubes, colonoscopy, enema or several voluminous oral capsules). Encapsulation of model bacteria strains in gel beads were first investigated. Then, the encapsulation method was applied to diluted stools. Robust spherical gel beads were obtained. The mean particle size was around 2 mm. A high loading of viable microorganisms was obtained for model strains and fecal samples. For plate-counting, values ranged from 10 15 to 10 17 CFU/g for single and mixed model strains, and 10 6 to 10 8 CFU/g for fecal samples. This corresponded to a viability of 30 % to 60 % as assessed by flow cytometry. This novel formulation is promising as the technology is applicable to both model strains and bacteria contained in the gut microbiota., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: co-author is a member of the editorial board of IJP - Eric Allémann., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Osteoarthritis (OA), the most common form of arthritis, is characterized by chronic inflammation, degeneration of articular cartilage and whole joints. Local delivery by intra-articular (IA) injection of small molecules is an established treatment to relieve pain and improve joint motion, requiring month-lasting release of therapeutic drug doses. We incorporated anti-inflammatory drug celecoxib in poly (D, L-lactic acid) microparticles using two spray-drying approaches - either as a solid drug solution or embedded as milled nano drug. Differential scanning calorimetry, X-ray powder diffraction, electron microscopy and in vitro drug release allowed comparison of the microparticles. Both types resulted in spherical particles ranging from 20 to 40 μm mean size, with high drug loadings (10% to 50% w/w) and entrapment efficiencies > 80%. However, after 90 days, in vitro celecoxib release from nano drug embedded microparticles presented a significantly slower release in comparison to drug in solution microparticles, attributed to the presence of stabilized amorphous drug. No cytotoxicity was observed in human articular synoviocytes and PGE 2 release was fully suppressed at low doses of both microparticulate systems. This study provides techniques to release high drug loads over months in a tunable manner, providing valuable options for the IA management of osteoarthritis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Advantages associated with the use of polylactic acid (PLA) nano- or microparticles as drug delivery systems have been widely proven in the field of pharmaceutical sciences. These biodegradable and biocompatible carriers have demonstrated different loading and release properties depending on interactions with the cargo, preparation methods, particles size or molecular weight of PLA. In this study, we sought to show the possibility of influencing these properties by modifying the structure of the constituting polymer. Seven non-functionalized or functionalized PLA polymers were specifically designed and synthesized by microwave-assisted ring-opening polymerization of d,l-lactide. They presented short hydrophobic and/or hydrophilic groups thanks to the use of C20 aliphatic chain, mPEG1000, sorbitan esters (Spans ® ) or polysorbates (Tweens ® ), their PEGylated analogues, as initiators. Then, seven types of drug-loaded nanoparticles (NP) were prepared from these polymers and compared in terms of physico-chemical characteristics, drug loading and release profiles. Although the loading properties were not improved with any of the functionalized PLA NP, different release profiles were observed in an aqueous medium at 37 °C and over a period of five days. The presence of PEG moieties in the core of PLA-polysorbates NP induced a faster release while the addition of a single aliphatic chain induced a slower release due to better interactions with the active molecule., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Following vascular bypass interventions, autologous saphenous vein grafts are prone to fail due to intimal hyperplasia development. An atorvastatin (ATV)-eluting tubular mesh coated with poly(d,l-lactide-co-glycolisde) acid (PLGA) was designed for perivascular application, in order to prevent the development of this pathology. Formulation parameters such as PLGA molecular weight, concentration of ATV and PLGA in the coating solution and number of coatings were investigated to optimise the mesh in terms of drug loading efficacy, drug release kinetics and mechanical properties. Using the dip-coating technique, 1.6 mg of ATV was loaded on a tubular 5 cm long mesh. The most important parameter influencing ATV loading was the concentration of the drug in the coating solution. In vitro an ATV release profile combining an initial fast release over 3 days and a sustained release over 40 days was obtained; consistent with the timeframe of hyperplasia development. The amount of PLGA polymer coating as well as the molecular weight of the polymer were optimized to achieve these kinetics. A poly(d,l-lactide-co-caprolactone) (PLCL) layer was sprayed on the external side of the PLGA coated tubular mesh to restrict the ATV release to the vascular tissue. Scanning electron microscopy observation showed that the macroporosity of the mesh was preserved after coating, while texture analysis demonstrated that its elasticity decreased slightly., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Small-molecule agonists for the Toll-like receptors (TLR) 7 and 8 are effective for the immunotherapy of skin cancer when used as topical agents. Their systemic use has however been largely unsuccessful due to dose-limiting toxicity. We propose a polymer-based nanodelivery system to target resiquimod, a TLR7 ligand, to the lymph node in order to focus the immunostimulatory activity and to prevent a generalized inflammatory response. We demonstrate successful encapsulation of resiquimod in methoxypoly(ethylene glycol)-b-poly(DL-lactic acid) (mPEG-PLA) and mixed poly(DL-lactic-co-glycolic acid) (PLGA)/mPEG-PLA nanoparticles. We show that these particles are taken up mainly by dendritic cells and macrophages, which are the prime initiators of anticancer immune responses. Nanoparticles loaded with resiquimod activate these cells, demonstrating the availability of the immune-stimulating cargo. The unloaded particles are non-inflammatory and do not have cytotoxic activity on immune cells. Following subcutaneous injection in mice, mPEG-PLA and PLGA/mPEG-PLA nanoparticles are detected in dendritic cells and macrophages in the draining lymph nodes, demonstrating the targeting potential of these particles. Thus, polymer-based nanoparticles represent a promising delivery system that allows lymph node targeting for small-molecule TLR7 agonists in the context of systemic cancer immunotherapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Intra-articular (IA) injection of extended drug release forms based on biodegradable microparticles holds promise for the treatment of joint diseases. However, the fate of microparticles following intra-articular injection is controversial and has not been thoroughly investigated. The aim of this work was therefore to evaluate the biodistribution of fluorescent poly(lactic acid) particles of different sizes after IA injection in arthritic or healthy mice. Regardless of the inflammatory status of the joint, 300 nm-nanoparticles leaked from the joint. Due to inflammation and related increase of vascular permeability, 3 μm-microparticles that were retained in the non-inflamed synovial membrane leaked from the inflamed joint. Complete retention of 10 μm-microparticles was observed independently of the joint inflammatory status. Embedding particles in a hyaluronic acid gel prolonged the retention of the formulations only in inflamed joints. Depending on particle's size, formulations were preferentially eliminated by blood vessels or lymphatic pathways. Poly(lactic acid) particles of 3 μm were biocompatible and retained in knee joints at least for 6 weeks. This work highlights the need to deliver hyaluronic acid-embedded particles of at least 3 μm to guarantee their retention in inflamed joints. These results will contribute to the rational design of long-lasting formulations to treat acute and chronic joint diseases., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Poly(D,L-lactic acid)-methoxypoly(ethylene glycol) (PLA-MePEG) copolymers were synthesized by ring-opening polymerization of D,L-lactide in the presence of MePEG of different molecular weights and stannous octoate as the catalyst. The chemical composition of the diblock-copolymer PLA-MePEG was confirmed by 1H-NMR and the molecular weight and distribution were assessed by gel permeation chromatography. Nanoparticles containing Nile red as a fluorescent dye were prepared using poly(D,L-lactic acid) (PLA), blends of PLA and PLA-MePEG or PLA-MePEG alone. Incubation of nanoparticles with human blood monocytes was performed in serum or in PBS and the cell-associated fluorescence was analyzed by flow cytometry. In serum, a protective effect was obtained and the interaction of particles with mononuclear leukocytes decreased to 40%., (Copyright 2002 Elsevier Science B.V.)

The aim of the present work was to find a suitable method for the introduction of thiol functions on the surface of poly(DL-lactic acid) (PLA) nanoparticles. Three different approaches were investigated. The modification of the surface involves the activation of PLA carboxylic acid groups followed by the attack of a nucleophile such as cysteine (method #1) or cystamine (method #2 and #3) that provide thiol functions via an amide bond. For the conjugation with cystamine, a second reaction step is required to expose the sulfhydryl function of cystamine that is otherwise protected in a disulfide bond. 1,4-Dithio-DL-threitol (DTT) (method #2) or Tris(2-carboxyethyl)-phosphine hydrochloride (method #3) were evaluated for their ability to reduce this linkage. Method #1 allowed a maximum of 8.5+/-2.8 mmol of thiol functions per mol of PLA to be attached on the surface of the nanoparticles. Method #2 allowed the introduction of a greater number of thiol functions (up to 190+/-15 mmol per mol of PLA). However, this latter method has a major drawback: DTT interacts strongly with the nanoparticle matrix during the reduction step. Method #3 has the advantage over method #2 in that it allowed a significant number of thiol functions to be covalently bound to the particles (up to 107.6+/-0.6 mmol per mol of PLA) without the problem of undesired interaction between DTT and the nanoparticle matrix. The introduction of thiol groups onto the surface of PLA nanoparticles is possible with all three suggested methods. The method #3 provides a straight forward approach for the substitution of carboxylic acid groups with a high number of activated sulfhydryl at the surface of PLA nanoparticles.

The feasibility of producing sterile and freeze-dried polyester nanoparticles was investigated. Various poly(D,L-lactide-co-glycolide) and poly(D,L-lactide) were selected as biodegradable polymers. Using the salting-out procedure, process parameters were optimized to obtain sub-200 nm particles. After purification, the nanoparticle suspensions containing different lyoprotectants were sterilized by filtration. Freeze-drying was performed using vials covered with 0.22 microm membrane filters in order to preserve the suspensions from bacterial contamination. Sterility was assessed on the final product according to pharmacopoeial requirements using the membrane filtration method. With all polymers tested, sub-200 nm particles could be obtained. Nanoparticles with a size as low as 102 nm were prepared with good reproducibility and narrow size distribution. Upon freeze-drying, it appeared that complete redispersion of all types of polyester nanoparticles could be obtained in presence of the lyoprotectants tested such as saccharides while aggregation was observed without lyoprotectant. Sterility testing showed no microbial contamination indicating that sterile nanoparticulate formulations have been achieved.

The aim of this study was to compare two methods to encapsulate a 25-mer-phosphorothioate oligonucleotide (ODN) into poly(D,L-lactic acid) (PLA) particles. Antisense oligonucleotides belong to a new therapeutic class especially attractive for the treatment of cancers and viral diseases. The development of these new drugs suffers, however, from poor stability in biological media and very low cellular uptake. Polymeric particulate systems display interesting features for ODN delivery. ODN are highly hydrophilic and most encapsulation methods are inappropriate for such molecules. Using poly(D,L-lactide) polymer, two methods of encapsulation were compared. First, a double emulsion technique was used to prepare nano- and microparticles. Secondly, the ODN was combined with a quaternary ammonium, the cethyltrimethyl-ammonium bromide (CTAB), to enhance the hydrophobicity of the molecule before entrapment by the emulsification-diffusion method. Both methods led to the formation of individualized and spherical particles loaded with a significant amount of ODN. Similar entrapment efficiencies were obtained for the nanoparticles prepared by both methods (approx. 27% of the theoretical loading) whereas 45% of entrapment efficiency was observed for the microparticles. Seventy five percent of the ODN were released in 60 min with the particles prepared by the emulsification-diffusion method, whereas only 7% were released in 60 h when using the double emulsion method. A viability test on U-937 cells showed better survival rates with the particles prepared by the double emulsion technique. The results suggest that the location of the ODN in the polymeric matrix is affected by the encapsulation method. Particles containing CTAB appeared more toxic than the ones obtained by the double emulsion technique, however, these particles can still be used for antisense activity since high oligonucleotide loading can be achieved.